A physiologically active hydrophobic substance having a low molecular weight such as a steroid hormone demonstrates its effect through an each individual nuclear receptor as a ligand thereof A group of nuclear receptor of steroid hormones forms a genetic superfamily and may control, i.e., activate or inhibit an expression of a target gene at transcriptional level through the function as a ligand-dependent transcriptional factor.
The steroid hormone receptors include a mineralocorticoid receptor (MR), a glucocorticoid receptor (GR), an androgen receptor (AR), an estrogen receptor (ER) and a progesterone receptor (PR). A steroid hormone, which is a ligand of the receptor such as a mineralocorticoid (aldosterone) or a glucocorticoid (cortisol etc.), shows various physiological functions through each receptor (Journal of Endocrinology, 2001; 169:pp. 437-445).
MR-specific ligand, aldosterone, is one of mediators in renin-angiotensin-aldosterone system (RAAS). Formerly, aldosterone has been considered to be nothing but a hormone which is produced only in adrenal glands and acts on distal urinary tubule to regulate water and sodium metabolism. However, recent studies proved that aldosterone is produced in various tissues such as heart, blood vessels, brain and the like and its receptors are widely distributed in cardiovascular tissues and the like. Besides, aldosterone is recognized as not only a precipitating factor of hypertension but also a risk hormone showing various impeding effects on cardiovascular tissues (e.g., cardiac fibrosis/necrosis, potentiation of catecholamine activity, deterioration of baroreceptor response).
In the recent large scale clinical trials (RALES and EPHESUS), it was confirmed that the concomitant use of an aldosterone receptor antagonist (eplerenone or spironolactone) with a conventional medicament such as an ACE inhibitor and the like significantly reduced hospitalization and mortality rate in patients with severe heart failure and significantly ameliorate the prognosis of patients with acute cardiac infarction (New England Journal of Medicine, 2003; 341: p. 709-717, New England Journal of Medicine, 2003; 348: p. 1309-1321). In this regard, it is considered that effective blockade of such hormone is important to establish the therapy of the cardiovascular diseases associated with aldosterone and its receptors.
As mentioned above, any ligands having an affinity to MR and activity of modulating the receptor function, namely repressors, antagonists, agonists, partial antagonists or partial agonists, may be useful as medicaments for prevention or treatment of the diseases or clinical states associated with aldosterone. On the other hand, a steroidal MR-ligand such as spironolactone or eplerenone has been often associated with specific and serious side effects (e.g., gynecomastia, irregular menses, erectile dysfunction), and therefore it has been desired to develop a compound having safety as a medicament without such side effects.
Up to now, 6H-dibenz[b,e]oxepine derivatives (WO2005/066161), dihydropyridine derivatives (WO2005/097118), dibenzo[b, d]pyrane derivatives (Bioorganic and Medicinal Chemistry Letters, 2004; 14: p. 2079-2082), 1,4-dihydro-2H-3,1-benzoxazin-6-yl-sulfonamide derivative (WO2006/077821) and the like have been known as a non-steroidal ligand having an affinity to MR. However, no fused bicyclic compound such as the compound of the present invention (a 1,3-benzoxazine derivative or a chromen derivative) having MR-modulating activity (e.g., MR-antagonizing activity) has been reported.
On the other hand, a 1,3-benzoxazine derivative or a chromen derivative is disclosed in e.g., U.S. Pat. No. 5,270,308, WO 2005/037830 and Journal of Medicinal Chemistry, 2002; 45(5): p. 1086-1097. In addition, the applicant already filed a patent application relating to 3,4-dihydro-1,4-benzoxazine derivatives having MR-modulating activity such as MR-antagonistic activity etc. (WO2007/089034) separately.